rs202183386

Variant names:

• chr10-62814181-T-G
• rs202183386
• NM_000399.5:c.457A>C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_000399.5(EGR2):​c.457A>C​(p.Thr153Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000125 in 1,613,932 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T153I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: EGR2 NM_000399.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:2
• Conservation: PhyloP100: 1.71
• Publications: 1 publications found

Genes affected

EGR2 (HGNC:3239): (early growth response 2) The protein encoded by this gene is a transcription factor with three tandem C2H2-type zinc fingers. Defects in this gene are associated with Charcot-Marie-Tooth disease type 1D (CMT1D), Charcot-Marie-Tooth disease type 4E (CMT4E), and with Dejerine-Sottas syndrome (DSS). Multiple transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Oct 2008]

EGR2 Gene-Disease associations (from GenCC):

• Charcot-Marie-Tooth disease type 4E

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• Charcot-Marie-Tooth disease

  Inheritance: SD Classification: DEFINITIVE Submitted by: ClinGen
• Charcot-Marie-Tooth disease type 1D

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• Charcot-Marie-Tooth disease type 3

  Inheritance: SD, AD Classification: MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.017387688).
• BP6: Variant 10-62814181-T-G is Benign according to our data. Variant chr10-62814181-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 462785.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000171 (26/152052) while in subpopulation NFE AF = 0.000147 (10/67964). AF 95% confidence interval is 0.0000792. There are 0 homozygotes in GnomAd4. There are 16 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000399.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EGR2	NM_000399.5	MANE Select	c.457A>C	p.Thr153Pro	missense	Exon 2 of 2	NP_000390.2
	EGR2	NM_001410931.1		c.496A>C	p.Thr166Pro	missense	Exon 3 of 3	NP_001397860.1	A0A8I5KYI5
	EGR2	NM_001136177.3		c.457A>C	p.Thr153Pro	missense	Exon 3 of 3	NP_001129649.1	P11161-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EGR2	ENST00000242480.4	TSL:1 MANE Select	c.457A>C	p.Thr153Pro	missense	Exon 2 of 2	ENSP00000242480.3	P11161-1
	EGR2	ENST00000439032.6	TSL:1	n.*472A>C		non_coding_transcript_exon	Exon 2 of 2	ENSP00000509775.1	A0A8I5KVU0
	EGR2	ENST00000439032.6	TSL:1	n.*472A>C		3_prime_UTR	Exon 2 of 2	ENSP00000509775.1	A0A8I5KVU0

Frequencies

GnomAD3 genomes AF: 0.000171 AC: 26 AN: 152052 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000199 AC: 50 AN: 251306 AF XY: 0.000214

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00387

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000880

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000120 AC: 176 AN: 1461880 Hom.: 0 Cov.: 31 AF XY: 0.000138 AC XY: 100 AN XY: 727236

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00379 AC: 99 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5766

European-Non Finnish (NFE) AF: 0.0000531 AC: 59 AN: 1112006

Other (OTH) AF: 0.000248 AC: 15 AN: 60394

GnomAD4 genome AF: 0.000171 AC: 26 AN: 152052 Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 16 AN XY: 74270

African (AFR) AF: 0.0000241 AC: 1 AN: 41410

American (AMR) AF: 0.00 AC: 0 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00432 AC: 15 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 67964

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.000585 Hom.: 0

Bravo AF: 0.000106

ExAC AF: 0.000173 AC: 21

EpiCase AF: 0.000382

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	-	1	Charcot-Marie-Tooth disease type 1D (1)
-	-	1	Charcot-Marie-Tooth disease, type I (1)
-	1	-	Dejerine-Sottas disease;C1843247:Charcot-Marie-Tooth disease type 1D;C4721436:Charcot-Marie-Tooth disease type 4E (1)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	T
Eigen	Benign	0.15
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.54	T
M_CAP	Benign	0.0070	T
MetaRNN	Benign	0.017	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		1.7
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.17
Sift	Benign	0.14	T
Sift4G	Uncertain	0.034	D
Polyphen		0.74	P
Vest4		0.25
MVP		0.62
MPC		1.2
ClinPred		0.080	T
GERP RS		3.9
Varity_R		0.41
gMVP		0.39
Mutation Taster		=54/46	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs202183386; hg19: chr10-64573941;